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Safety Announcement Concerning TNF Blockers

Note from CCFA' Patient Education Committee: The risk of these lymphomas are quiet rare, and the benefit to an individual of these medications in most cases far outweigh the risk. Patients/Families should discuss the risk and benefits of these medications with their doctor. Additional information regarding assessing the risks and benefits of all IBD treatments is available through the "Balancing the Risks and Benefits of Treatment in Inflammatory Bowel Diseases teleconference or by contacting the Information Resource Center info@ccfa.org

[04-14-2011] The U.S. Food and Drug Administration (FDA) is informing the public that it continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn's disease and ulcerative colitis with medicines known as tumor necrosis factor (TNF) blockers, as well as with azathioprine, and/or mercaptopurine.

Crohn's disease and ulcerative colitis cause inflammation of the digestive system. Common symptoms are pain in the abdomen, cramps, and diarrhea. Bleeding from the rectum, weight loss, joint pain, skin problems and fever also may occur. Children with the disease may have growth problems, develop intestinal blockage, and experience malnutrition.1

Facts about TNF Blockers, Azathioprine, and Mercaptopurine

TNF blockers suppress the immune system by blocking the activity of TNF, a substance in the body that can cause inflammation and lead to immune-system diseases, such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. The drugs in this class include Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol) and Simponi (golimumab).

Azathioprine (also known as Imuran) and mercaptopurine (known as Purinethol) also suppress the immune system. They are commonly used as part of a combination regimen or used alone to treat Crohn's disease and ulcerative colitis, although they are not approved for those uses.

Azathioprine is approved for the prevention of rejection following renal transplantation and for the reduction of signs and symptoms of rheumatoid arthritis.

Mercaptopurine is approved to treat acute lymphatic leukemia.

HSTCL is an aggressive (fast-growing) cancer and is usually fatal. The majority of cases reported were in patients being treated for Crohn's disease or ulcerative colitis, but also included a patient being treated for psoriasis and two patients being treated for rheumatoid arthritis. FDA is now updating the number of reported cases of HSTCL.

Although most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system, including the TNF blockers, azathioprine, and/or mercaptopurine, there have been cases reported in patients receiving azathioprine or mercaptopurine alone.

FDA believes the risks and benefits of using TNF blockers, azathioprine, and/or mercaptopurine should be carefully weighed when prescribing these drugs to children and young adults, especially for the treatment of Crohn's disease and ulcerative colitis. Patients should continue to talk to their Healthcare Professionals about the potential risk of HSTCL with use of these medications in order to make the best decision about their medical treatment.

FDA previously communicated about the increased risk of lymphomas and other cancers associated with the use of TNF blockers in children and adolescents in June 2008 and in August 2009 when warnings were added to the TNF blocker labels.

The product labels for Remicade (infliximab) and Humira (adalimumab) have been updated and the product labels for azathioprine and mercaptopurine are being updated to include warnings about HSTCL that have been reported in patients treated with these products.

FDA will continue to communicate any new safety information to the public as it becomes available.

Additional Information for Patients

Be aware that taking TNF blockers, azathioprine, and/or mercaptopurine may increase the risk of HSTCL.

Review the Medication Guide that accompanies a prescription for TNF blockers.

Discuss any questions or concerns about these medications with your healthcare professional.

Report any side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.

Additional Information for Healthcare Professionals

Discuss with patients and caregivers the increased risk of developing HSTCL, especially in adolescents and young adults, taking into account the risks/benefits of TNF blockers, azathioprine, and/or mercaptopurine, and other immunosuppressive therapies.

Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.

Monitor for the emergence of malignancies when a patient has been treated with TNF blockers, azathioprine, and/or mercaptopurine.

Know that people with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis may be more likely to develop lymphoma than the general U.S. population. Therefore, it may be difficult to measure the added risk of TNF blockers, azathioprine, and/or mercaptopurine.

Report adverse events involving TNF blockers, azathioprine and/or mercaptopurine to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.

Data Summary

FDA is updating the public about the number of reported cases of Hepatosplenic T-cell Lymphoma (HSTCL). From initiation of TNF blocker marketing to December 31, 2010, the following HSTCL cases have been identified in the Adverse Event Reporting System (AERS) database (de-duplicated), the literature, and the HSTCL Cancer Survivors' Network in association with the following agents (mutually exclusive): Infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0), azathioprine (12), and mercaptopurine (3). Of note, in the 20 cases identified with infliximab use, 18 of the patients also were using concomitant mercaptopurine or azathioprine (for the remaining two patients, concomitant drug use was not reported). Of the 5 cases identified with infliximab/adalimumab use, 4 patients were using concomitant mercaptopurine or azathioprine (for the remaining patient, concomitant drug use was not reported). Complete medical histories have not been obtained on some cases to exclude a history of exposure to a potential confounder/co-factor. See Table 1 for the list of cumulative cases associated with selected immunosuppressant use reported as of December 31, 2010.

Due to the potential increased risk for cancers, including HSTCL, the risks and benefits of using TNF blocker products, azathioprine and/or mercaptopurine should be carefully weighed when prescribing these drugs especially in adolescents and young adults.

References

U.S. National Library of Medicine. National Institutes of Health. Crohn's Disease health topic. Available here. Accessed March 1, 2011.

TABLE 1. Cumulative Cases of HSTCL Associated with Selected Immunosuppressant Use† Reported to the Adverse Event Reporting System, the Published Literature, and HSTCL Cancer Survivor's Network as of December 31, 2010

Product Indication for use Sex Patient age in years Duration of use Concomitant agent Outcome

Infliximab§

N=20 CD (17), UC (3) M (17)1, 2, 3, 4

F (3)5 Median =30,

Range=12 to 74 Range: 1 dose to intermittent use for 7-8 years(doses not specified) (19), not stated (1) 18 (azathioprine or mercaptopurine)* Death (17)Infliximab/ada-limumab§

15 HSTCL Cancer Survivors Network, csn.cancer.org/node/136135, accessed on June 25, 2010 (search identified 2 patients treated for UC and 1 patient treated for CD; note that these cases have not been verified by a health care professional).

Crohn's & Colitis Foundation

The Crohn's & Colitis Foundation of America's mission is to cure Crohn's disease and ulcerative colitis, and to improve the quality of life of children and adults affected by
these diseases. The Foundation ranks third among leading health non-profits in the percentage of expense devoted to research toward a cure, with more than 80 cents of
every dollar the Foundation spends going to mission-critical programs. The Foundation consistently meets the standards of organizations that monitor charities, including the
Better Business Bureau's Wise Giving Alliance (give.org) and the American Institute of Philanthropy (charitywatch.org).